Artesunate in glioblastoma therapy: Case reports and review of clinical studies.

BACKGROUND: Artesunate, a derivative of the active ingredient artemisinin from Artemisia annua L. used for centuries in the traditional Chinese medicine, is being applied as front-line drug in malaria treatment. As it is cytotoxic for cancer cells, trials are ongoing to include this drug as supplement in cancer therapy. In glioblastoma cells, artesunate was shown to induce oxidative stress, DNA base damage and double-strand breaks (DSBs), apoptosis, and necroptosis. It also inhibits DNA repair functions and bears senolytic activity. Compared to ionizing radiation, DNA damages accumulate over the whole exposure period, which makes the agent unique in its genotoxic profile. Artesunate has been used in adjuvant therapy of various cancers. PURPOSE: As artesunate has been used in adjuvant therapy of different types of cancer and clinical trials are lacking in brain cancer, we investigated its activity in glioma patients with focus on possible side effects. STUDY DESIGN: Between 2014 and 2020, twelve patients were treated with artesunate for relapsing glioma and analyzed retrospectively: 8 males and 4 females, median age 45 years. HISTOLOGY: 4 glioblastomas WHO grade 4, 5 astrocytomas WHO grade 3, 3 oligodendrogliomas grade 2 or 3. All patients were pretreated with radiation and temozolomide-based chemotherapy. Artesunate 100 mg was applied twice daily p.o. combined with dose-dense temozolomide alone (100 mg/m2 day 1-5/7, 10 patients) or with temozolomide (50 mg/m2 day 1-5/7) plus lomustine (CCNU, 40 mg day 6/7). Blood count, C-reactive protein (CRP), liver enzymes, and renal parameters were monitored weekly. RESULTS: Apart from one transient grade 3 hematological toxicity, artesunate was well tolerated. No liver toxicity was observed. While 8 patients with late stage of the disease had a median survival of 5 months after initiation of artesunate treatment, 4 patients with treatment for remission maintenance showed a median survival of 46 months. We also review clinical trials that have been performed in other cancers where artesunate was included in the treatment regimen. CONCLUSIONS: Artesunate administered at a dose of 2 × 100 mg/day was without harmful side effects, even if combined with alkylating agents used in glioma therapy. Thus, the phytochemical, which is also utilized as food supplement, is an interesting, well tolerated supportive agent useful for long-term maintenance treatment. Being itself cytotoxic on glioblastoma cells and enhancing the cytotoxicity of temozolomide as well as in view of its senolytic activity, artesunate has clearly a potential to enhance the efficacy of malignant brain cancer therapy.

Identification of resibufogenin, a component of toad venom, as a novel senolytic compound in vitro and for potential skin rejuvenation in male mice.

Senescent cells that accumulate with age have been shown to contribute to age-related diseases and organ dysfunction and have attracted attention as a target for anti-aging therapy. In particular, the use of senescent cell-depleting agents, or senolytics, has been shown to improve the aging phenotype in animal models. Since senescence has been implicated in the skin, particularly in fibroblasts, this study used aged human skin fibroblasts to investigate the effects of resibufogenin. A component of the traditional Chinese medicine toad venom, resibufogenin was investigated for senolytic and/or senomorphic activity. We found that the compound selectively caused senescent cell death without affecting proliferating cells, with a marked effect on the suppression of the senescence-associated secretory phenotype. We also found that resibufogenin causes senescent cell death by inducing a caspase-3-mediated apoptotic program. Administration of resibufogenin to aging mice resulted in an increase in dermal collagen density and subcutaneous fat, improving the phenotype of aging skin. In other words, resibufogenin ameliorates skin aging through selective induction of senescent cell apoptosis without affecting non-aged cells. This traditional compound may have potential therapeutic benefits in skin aging characterized by senescent cell accumulation.

A Cocktail of Polyherbal Bioactive Compounds and Regular Mobility Training as Senolytic Approaches in Age-dependent Alzheimer's: the In Silico Analysis, Lifestyle Intervention in Old Age.

Alzheimer's is a principal concern globally. Machine learning is a valuable tool to determine protective and diagnostic approaches for the elderly. We analyzed microarray datasets of Alzheimer's cases based on artificial intelligence by R statistical software. This study provided a screened pool of ncRNAs and coding RNAs related to Alzheimer's development. We designed hub genes as cut points in networks and predicted potential microRNAs and LncRNA to regulate protein networks in aging and Alzheimer's through in silico algorithms. Notably, we collected effective traditional herbal medicines. A list of bioactive compounds prepared including capsaicin, piperine, crocetin, safranal, saffron oil, coumarin, thujone, rosmarinic acid, sabinene, thymoquinone, ascorbic acid, vitamin E, cyanidin, rhaponticin, isovitexin, coumarin, nobiletin, evodiamine, gingerol, curcumin, quercetin, fisetin, and allicin as an effective fusion that potentially modulates hub proteins and molecular signaling pathways based on pharmacophore model screening and chemoinformatics survey. We identified profiles of 21 mRNAs, 272 microRNAs, and eight LncRNA in Alzheimer's based on prediction algorithms. We suggested a fusion of senolytic herbal ligands as an alternative therapy and preventive formulation in dementia. Also, we provided ncRNAs expression status as novel monitoring strategies in Alzheimer's and new cut-point proteins as novel therapeutic approaches. Synchronizing fusion drugs and lifestyle could reverse Alzheimer's hallmarks to amelioration via an offset of the signaling pathways, leading to increased life quality in the elderly.

Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan.

Disrupted biological function, manifesting through the hallmarks of aging, poses one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease in nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds, to restore NAD+ levels present in youth. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through the inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NAD+ precursor supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.

Oridonin acts as a novel senolytic by targeting glutathione S-transferases to activate the ROS-p38 signaling axis in senescent cells.

Most of the known senolytics are anti-cancer drugs or their derivative molecules. However, senolytics derived from the active ingredients of traditional Chinese medicine (TCM) are rarely reported. Here, we identified oridonin as a novel senolytic and further revealed that it might target a class of glutathione S-transferases to activate ROS-p38 signaling and induce apoptosis in senescent cells.

Isatis tinctoria L. Leaf Extract Inhibits Replicative Senescence in Dermal Fibroblasts by Regulating mTOR-NF-κB-SASP Signaling.

Senescent fibroblasts progressively deteriorate the functional properties of skin tissue. Senescent cells secrete senescence-associated secretory phenotype (SASP) factor, which causes the aging of surrounding non-senescent cells and accelerates aging in the individuals. Recent findings suggested the senomorphic targeting of the SASP regulation as a new generation of effective therapeutics. We investigated whether Isatis tinctoria L. leaf extract (ITE) inhibited senescence biomarkers p53, p21CDKN1A, and p16INK4A gene expression, and SASP secretions by inhibiting cellular senescence in the replicative senescent human dermal fibroblast (RS-HDF). ITE has been demonstrated to inhibit the secretion of SASP factors in several senomorphic types by regulating the MAPK/NF-κB pathway via its inhibitory effect on mTOR. ITE suppressed the inflammatory response by inhibiting mTOR, MAPK, and IκBα phosphorylation, and blocking the nuclear translocation of NF-κB. In addition, we observed that autophagy pathway was related to inhibitory effect of ITE on cellular senescence. From these results, we concluded that ITE can prevent and restore senescence by blocking the activation and secretion of senescence-related factors generated from RS-HDFs through mTOR-NF-κB regulation.

Interplay between Inflammaging, Frailty and Nutrition in Covid-19: Preventive and Adjuvant Treatment Perspectives.

As humans age, their immune system undergoes modifications, including a low-grade inflammatory status called inflammaging. These changes are associated with a loss of physical and immune resilience, amplifying the risk of being malnourished and frail. Under the COVID-19 scenario, inflammaging increases the susceptibility to poor prognostics. We aimed to bring the current concepts of inflammaging and its relationship with frailty and COVID-19 prognostic; highlight the importance of evaluating the nutritional risk together with frailty aiming to monitor older adults in COVID-19 scenario; explore some compounds with potential to modulate inflammaging in perspective to manage the COVID-19 infection. Substances such as probiotics and senolytics can help reduce the high inflammatory status. Also, the periodic evaluation of nutrition risk and frailty will allow interventions, assuring the appropriate care.

Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs.

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis (OA). In this study, we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs (DMOADs). Specifically, human bone marrow-derived mesenchymal stromal cells (MSCs) were expanded in vitro up to passage 10 (P10-MSCs). Following their senescent phenotype formation, P10-MSCs were subjected to pellet culture in chondrogenic medium. Results from qRT-PCR, histology, and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents, when compared to that from normal passage 4 (P4)-MSCs. Interestingly, the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples, as demonstrated by RNA Sequencing data and other analysis methods. Lastly, the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics. The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage. The P4- and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.

Strategies for late phase preclinical and early clinical trials of senolytics.

Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.

Vitagenic Effect of Specific Bioactive Fractions of Rhodiola with Trachurus sp. Extract Against Oxidative Stress-Induced Aging in Human Amnion Derived Epithelial Cell Line: In View of a Novel Senolytic.

BACKGROUND: Rhodiola rosea is a herb that has been used in traditional medicine for several years, and LF is a class of lipoproteins derived from the fish Trachurus sp. (LF-T), which exhibits known anti-inflammatory activity. OBJECTIVE: Investigating the anti-aging effect of Rhodiola specific bioactive fractions cluster in combination with LF-T (R-L compound) in H2O2 mediated oxidative stress-induced human amnion derived epithelial cell line - FL cells as normal human cell line. METHODS: FL cells were treated with H2O2 to induce cellular aging, followed by treatment of the RL compound to study its anti-aging characteristics. Based on the proliferation rate, 0.05% and 0.1% concentration of R-L compound was determined using MTT assay. Anti-aging and anti-oxidant assays, ABTS, DPPH, Hyaluronidase activity Nitric Oxide, Lipid Peroxidase, and Superoxide Dismutase were performed. qPCR for anti-aging genes and matrix metalloproteinase genes were analyzed. RESULTS: FL cells treated with R-L compound exhibited increased proliferation rate and free-radical reduction. Decreased Hyaluronidase enzyme activity and regulation of genes such as SIRT1, KLOTHO, SERPINA 6, MMP 9, and MMP 2 expression depicted the anti-aging role of the R-L compound. Chemometric profiling of the R-L compound revealed that aromatic compounds and unsaturated fatty acids along with their derivatives, were present predominantly, which might have attributed to the potent oxidative stress impeded aging activity. CONCLUSION: Specific Bioactive Fractions of Rhodiola in combination with LF-T obtained from Trachurus sp. involve in the regulation of aging genes and might be a novel approach to prevent the cells from oxidative stress damage and also it might avert the aging of cells.